Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer's disease

Abstract

Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer's disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.

Keywords: Alzheimer’s disease; PPAD; Porphyromonas gingivalis; atherosclerosis; citrullination; deimination; periodontitis; rheumatoid arthritis.

Figure 1.

Schematic to show additive effect from an oral condition such as periodontitis to the development of mixed pathologies through smoking, atherosclerosis, and rheumatoid arthritis with direct inflammatory mediator input from P. gingivalis infection to Alzheimer’s disease. The major arrows point to major risk factors with plausible effect on each condition. The three-way arrows provide explanation of the link with periodontitis.

Figure 2.

Chemical modification of arginine amino acid residue by P. gingivalis and host-mediated peptidylarginine deiminases resulting in the conversion of arginine on functional peptide to citrulline (defective protein). This posttranslational modification alters the spatial arrangement of the original 3D-structure and function of the protein peptide as indicated by arrows (arginine-peptide and citrulline-peptide). Ammonia released during the chemical reaction is beneficial for PPAD activation.

Figure 3.

Schematic to illustrate immune events leading to autoimmunity resulting from PPAD-mediated citrullination of C-terminal arginine residues. These citrullinated peptides produced by the combined action of gingipains cleave polypeptides into fragments. This results in PPAD structurally becoming closer to gingipains on the bacterial surface membrane. P. gingivalis also citrullinates its own proteins generated by PPAD. These represent a pool of potent antigenic epitopes that can break the tolerance to specific citrullinated host peptides. The loss of tolerance can generate autoantibodies against citrullinated proteins. The arrows point to direction(s) of immune processes with the endpoint being autoimmunity. Text in boxes clarifies the symbols alongside the cascade of events as visualized by the authors. TLR 2/4 = toll like receptors 2 and 4, MD-2 = adapter protein in the NFkB inflammatory cascade, EGF = epidermal growth factor.